Int J Cardiovasc Imaging (2015) 31:727–731
DOI 10.1007/s10554-015-0608-z
ORIGINAL PAPER
The influence of lidocaine topical anesthesia
during transesophageal echocardiography on blood
methemoglobin level and risk of methemoglobinemia
Dominika Filipiak-Strzecka • Jarosław D. Kasprzak
Marta Wiszniewska • Jolanta Walusiak-Skorupa •
Piotr Lipiec
Received: 30 December 2014 / Accepted: 28 January 2015 / Published online: 7 February 2015
Ó The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract Methemoglobinemia is a relatively rare, but
potentially life-threating medical condition, which may be
induced by application of topical anaesthetic agents com-
monly used during endoscopic procedure. The aim of our
study was to assess the influence of lidocaine used prior to
transesophageal echocardiography (TEE) on the blood level
of methemoglobin in vivo. Additionally we attempted to
establish the occurrence rate of clinically evident lidocaine-
induced methemoglobinemia on the basis of data collected in
our institution. We retrospectively analyzed patient records
from 3,354 TEEs performed in our echocardiographic
laboratory over the course of 13 years in search for clinically
evident methemoglobinemia cases. Additionally, 18 con-
secutive patients referred for TEE were included in the
prospective part of our analysis. Blood samples were tested
before and 60 min after pre-TEE lidocaine anesthesia ap-
plication. Information concerning concomitant conditions
and pharmacotherapy were also obtained. In 3,354 patients
who underwent TEE in our institution no cases of clinically
evident methemoglobinemia occurred. In the prospective
part of the study, none of 18 patients [16 (89 %) men, mean
age 63 ± 13] was diagnosed with either clinical symptoms
of methemoglobinemia or exceeded normal blood concen-
tration of methemoglobin. Initial mean methemoglobin level
was 0.5 ± 0.1 % with mild, statistically (but not clinically)
D. Filipiak-Strzecka (&)
J. D. Kasprzak
P. Lipiec
Department of Cardiology, Bieganski Hospital, Medical
University of Lodz, Kniaziewicza 1/5, 91-347 Lodz, Poland
e-mail: dominika.filipiak@gmail.com
M. Wiszniewska
J. Walusiak-Skorupa
Department of Occupational Diseases, Nofer Institute of
Occupational Medicine, Lodz, Poland
•
significant rise to 0.6 ± 0.1 % after 60 min (p = 0.02).
Among the analyzed factors only the relation between the
proton pump inhibitors intake and methemoglobin blood
level rise was identified as statistically relevant (p = 0.03).
In adults, pre-TEE lidocaine anesthesia with recommended
dosage results in significant increase in methemoglobin
blood level, which however does not exceed normal values
and does not result in clinically evident methemoglobinemia.
Keywords Methemoglobinemia
Transesophageal
echocardiography
Lidocaine
Local anesthesia
Introduction
Methemoglobinemia is a relatively rare, but potentially
life-threating medical condition, especially if not recog-
nized and treated immediately [1–4]. It is defined by in-
creased concentration of an oxidized form of hemoglobin
in which the heme iron exists in the ferric (Fe?3) state
[5]. This form of hemoglobin is not only unable to bind
oxygen but also shifts the oxygen-hemoglobin disso-
ciation curve to the left and changes its sigmoid shape
into a more hyperbolic one, thus impairing oxygen ex-
traction in the tissues [6]. Therefore, excessive replace-
ment of hemoglobin with methemoglobin leads to
functional anemia and tissue hypoxia. First symptoms are
cyanosis, low pulse oximetric readings, and chocolate-
brown color of arterial blood sampling with normal ar-
terial PO2 values. Clinically, patients may suffer from
shortness of breath, cough and dizziness. In case of severe
methemoglobinemia episode, with methemoglobin level
exceeding 55 %, patients may develop lethargy, stupor,
and deteriorating consciousness. Higher levels (methe-
moglobin level [70 %) may result in dysrhythmias,
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circulatory failure, neurological depression, which in ex-
treme cases could be lethal [7]. The diagnosis is estab-
lished by measuring methemoglobin levels using CO-
oximetry in the arterial or venous blood [8].
In normal conditions methemoglobin rarely exceeds the
level of 1.5 % of total hemoglobin content, considered as
an upper limit of normal value.
The causes of methemoglobinemia may be congenital
(hereditary enzymatic disorders) or acquired. The latter
may occur after exposure to toxins or drugs. Agents may be
divided into direct oxidizers, capable of inducing methe-
moglobin formation when added to erythrocytes both
in vitro or in vivo, and indirect oxidizers, which do not
induce methemoglobin formation when exposed to ery-
throcytes in vitro, but do so after metabolic modification
in vivo [9]. The example of indirect oxidizers are local
anesthesia agents.
Local anesthetics are routinely administered in na-
sopharyngeal and oropharyngeal anesthesia, prior to en-
doscopic procedures [10]. The vast majority of reported
methemoglobinemia cases related with exposure to anes-
thetic drugs occurred after benzocaine administration.
Therefore certain authors suggested that benzocaine should
no longer be used as topical anesthetic for mucosa [11, 12].
Lidocaine appears to be a safer alternative, however its
ability to induce methemoglobin formation remains un-
known. The aim of our study was to assess the influence of
standard dose of lidocaine used for anesthesia of pharyn-
geal mucosa prior to transesophageal echocardiographic
examination (TEE) on the level of methemoglobin. Addi-
tionally we attempted to retrospectively establish the oc-
currence rate of clinically evident lidocaine-induced
methemoglobinemia using a retrospective analysis of the
databases in our institution.
0,85
Mean
0,80 Mean ±Statistical error
0,75
Mean ±2*Standard deviation
Methemoglobin level [%]
0,70
0,65
0,60
0,55
0,50
0,45
0,40
0,35
0 minute
Fig. 1 Plot of changes in methemoglobin level before and 60 min
after administration of lidocaine
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Int J Cardiovasc Imaging (2015) 31:727–731
Methods
TEE protocol
The protocol applied in our institution for pre-TEE orophar-
ygeal anesthesia is based on direct application of 10 % li-
docaine spray (2 doses—9.6 mg of pure lidocaine) while the
ultrasonographic gel used during the examination does not
contain any anesthetics. Saturation is continuously monitored
during the procedure by means of finger pulsoximetry.
The majority of patients undergoing TEE in our echo
laboratory are hospitalized due to concomitant conditions
and remain in our department for at least 24 h. Should the
examination be performed as an outpatient procedure, it is
followed by 2 h of clinical observation. If no adverse ef-
fects occur, patients are discharged after being informed
about the obligation to report to the emergency department
of our institution if deteriorate clinically.
Database analysis
We aimed to identify all cases of clinically evident
methemoglobinemia ensuing after TEE performed at our
institution in the period between January the 1st of 2000
and 14th October 2013. To achieve this we have analyzed
the echocardiography database as well as electronic med-
ical records of our department in search of methe-
moglobinemia diagnosis. To minimize the risk of
overlooking the cases of methemoglobinemia which may
have occurred after hospital discharge, Emergency
Department database was also included in the analysis.
Prospective analysis
Eighteen consecutive patients [16 (89 %) men, mean age
63 ± 13] hospitalized in our department, with clinical need
for TEE, were enrolled in the study. All subject signed an
informed consent form. Before the examination onset a
questionnaire based clinical history inclusive of age, sex,
weight, height, episodes of fever [38 °C within the last
7 days, chronic renal disease, heart failure, ischemic heart
disease, nitrate/oral hypoglycemic/proton pump inhibitors
pharmacotherapy (which was considered as a potential risk
factor of methemoglobinemia in the previous studies [8,
13, 14]), hypersensitivity to local anesthesia or previous
episodes of methemoglobinemia was collected from all
participants. The sole exclusion criterion was exposure to
local anesthesia agents within previous 7 days.
Indication for TEE study and current hemoglobin level
(test performed within 24 h) were extracted from medical
60 minute
records.
Fourteen patients were referred to TEE prior to car-
dioversion in order to rule out the suspicion of thrombus in
Int J Cardiovasc Imaging (2015) 31:727–731 729

left atrium appendage (in one case the thrombus was de-
tected in TEE); in three patients TEE was a part of valvular
diseases diagnostics, in one patient atrial septum defect was
suspected after transthoracic echocardiography examina-
tion. None of the patients manifested the clinical symptoms
of infective endocarditis. Mean level of hemoglobin in the
study population was 14.6 ± 1.7 mg/dl (range 11.2–17.8
mg/dl), mean O2 saturation was 97 ± 1 % (range
94–97 %).
One patient reported increase in body temperature
[38 °C within 7 days preceding the examination. Chronic
renal disease, heart failure, ischemic heart disease were
present in medical history of two, three and four patients,
respectively. One patient received a chronic long-acting
nitrate therapy, two patients were treated with oral hypo-
glycemics and nine with proton pump inhibitors.
Prior to the previously described topical anesthesia
protocol preceding TEE, a blood sample (1 ml anaerobi-
cally in a Vaculette Lithium Heparine blood syringe) was
taken from each patient.
16 out of 18 patients received sedation (midazolam in-
travenously, mean dose 3.4 mg, range 2–5 mg).
Having completed the echocardiographic examination,
we drew another blood sample from another puncture site
after 60 min from lidocaine application. Both blood sam-
ples were immediately placed in the cool and dry envi-
ronment (temperature 5 °C). Samples were tested for
methemoglobin level with a Cobas b 211 (Roche Diag-
nostic) diagnostic workstation. Measurement is based on
the relation between characteristic absorption of he-
moglobin derivative and the wave length according to
Lambert–Beer law. This instrument reports the methe-
moglobin level to the nearest tenth of a percent.
Statistical analysis
Data were stored and statistical analyses performed using
Statistica version 10.0 (StatSoft Poland, Cracow, Poland)
by means of simple descriptive statistics and Wilcoxon and
Man-Whitney statistical test. p value\0.05 was considered
statistically significant.
Results
Datebase analysis
The total of 3,354 TEE were performed during the period
between 1st January 2000 and 14th October 2013 [1,911
(57 %) men, mean age 56 ± 16]. In 115 (3.4 %) cases the
referral diagnosis was infective endocarditis and in 252
(7.5 %) cases there was a thrombus present in heart
cavities. No cases of methemoglobinemia could be iden-
tified in discussed group.
Prospective analysis
None of 18 patients revealed clinical symptoms of
methemoglobinemia. The post-lidocaine values of methe-
moglobin level remained in all patients below the upper
normal limit for methemoglobin (1.5 %).
Initial mean methemoglobin level was 0.5 ± 0.1 %
(range 0.4–0.6 %) whereas after 60 min it reached the
mean level of 0.6 ± 0.1 % (range 0.5–0.9 %) which rep-
resented a statistically significant change (p = 0.02, Wil-
coxon test) (Fig. 1).
Subsequently the correlation between above mentioned
clinical variables pharmacotherapy and rise of methe-
moglobin blood level was tested (Mann–Whitney test,
Table 1). Among the analyzed factors only the relationship
between the treatment with proton pump inhibitors and
methemoglobin blood level rise could be qualified as sta-
tistically relevant (mean change in methemoglobin level in
patients taking proton pump inhibitors: 0.13 ± 0.12 %,
range 0–0.4 %; in the remaining patients: 0.01 ± 0.09 %,
range 0.1–0.2 %; p value 0.03).
Discussion
To the best of our knowledge this study is the first one to
prospectively analyze the influence of pre-TEE lidocaine
exposure on the blood methemoglobin content and occur-
rence of clinical methemoglobinemia. On the basis of the
results of our prospective analysis combined with retro-
spective study of our institution databases the following
Table 1 Characteristics of prospective study population
Number of patients
Total number of patients 18
Male sex 16 (89 %)
Mean age (years) 63 ± 13
Fever [38 °C within the last 7 days 1 (5.6 %)
Chronic renal disease 2 (11.1 %)
Heart failure 3 (16.7 %)
Ischemic heart disease 4 (22.2 %)
Pharmacotherapy
Nitrate 1 (5.6 %)
Oral hypoglycemic 2 (11.1 %)
Proton pump inhibitors 9 (50 %)
Hypersensitivity to local anesthesia 0
Previous episodes of methemoglobinemia 0

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findings may be issued: (1) Pre-TEE exposure to recom-
mended lidocaine doses results in statistically significant
increase of methemoglobin blood level which however
does not exceed normal values. (2) Lidocaine administered
in recommended doses is a relatively safe local anesthetic
agent for oropharyngeal topical anesthesia in patients un-
dergoing TEE.
Four types of local anesthetics have been suspected as
possible cause of methemoglobinemia: prilocaine, benzo-
caine, lidocaine, and tetracaine. Its occurrence may be pos-
sibly related to a number of clinical factors such as age, dose
of medication, enzyme deficiencies, malnutrition, mucosal
erosion, hospitalization, sepsis, and anemia [7]. However,
during the endoscopic procedures, agents most commonly
used for oropharyngeal anesthesia are either benzocaine or
lidocaine spray. Systematic reviews published up to date, as
well as case-reports, indicate the significantly higher
methemoglobinemia occurrence rate related with benzo-
caine exposure than with lidocaine anesthesia. In a review
presenting 242 cases of local anesthesia–related methe-
moglobinemia 159 (65.7 %) patients were anesthetized with
agents containing benzocaine, among which 105 (43.4 %)
patients were treated with benzocaine alone. 12 incidents of
methemoglobinemia were initially connected with lidocaine
application, however only three patients episode could not be
attributed with any other cause than topical lidocaine ad-
ministration [12, 15–17].
In another study analyzing 24,431 patients undergoing
endoscopic procedures, no cases of methemoglobinemia
occurred among 22,210 patients anesthetized with 4 % li-
docaine spray prior to upper gastrointestinal endoscopy/
bronchoscopy. Adversely, in the second group consisting
of 2,221 patients in whom 20 % benzocaine spray anes-
thesia was performed prior to TEE, nine cases of clinically
significant methemoglobinemia were reported [11], a sig-
nificant difference in risk.
Similarly, in our population of 3,354 patients undergoing
TEE during the last 13 years not a single case of clinically
manifesting methemoglobinemia was detected. Due to ret-
rospective character of database analysis there is a theoretical
possibility of discarding the events of methemoglobinemia in
patients who were not hospitalized after the TEE. However,
the number of such patients did not exceed 15 % of total
retrospective analysis population. Furthermore, if they had
developed clinical methemoglobinemia, their records should
have been included into ER source data.
Methemoglobinemia associated with lidocaine has been
shown to be caused by metabolites produced from xylidine
after it has been hydrolyzed from lidocaine [18]. However,
only a part of absorbed lidocaine is hydrolyzed to xylidine.
Furthermore, in a recent in vitro study based on the incu-
bation of benzocaine, lidocaine and xylidine with whole
human blood and pooled human liver S9, authors have
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Int J Cardiovasc Imaging (2015) 31:727–731
observed that benzocaine produces much more methe-
moglobin than lidocaine or xylidine [19].
Maximal acceptable dose of lidocaine used subcuta-
neously or intravenously is 200 mg (4.5 mg/kg of body
mass). It could be assumed that during topical mucosal
anesthesia the lidocaine dose is not completely absorbed;
furthermore, doses routinely used prior to endoscopic
procedures are significantly smaller. Patients included in
our study received ca. 10 mg of pure lidocaine regardless
of body weight (max. 0.15 mg/kg of body mass). Although
none of them developed methemoglobinemia, a statisti-
cally significant increase in methemoglobin blood level
was detected. Thus, it can be assumed that although lido-
caine is considered a safe topical mucosa anesthetic, its
dose should be carefully adjusted and minimal effective
dose should be administered in all cases [20].
Our echocardiography suite has no experience or clin-
ical data regarding the benzocaine anesthesia as it has
never been used for the purpose discussed.
In conclusion, pre-TEE lidocaine anesthesia with a dose
close to 10 % of maximal accepted produced statistically
relevant but clinically insignificant increase in methe-
moglobin blood level. According to our data lidocaine is a
relatively safe topical anesthetic agent. This corresponds
well with findings of up-to-date scientific literature sug-
gesting that lidocaine is less likely to cause methe-
moglobinemia than benzocaine when used during certain
endoscopic procedures. Therefore it may be beneficial for
the patients to consider lidocaine as a medicine of choice
for topical oropharyngeal mucosa anesthesia.
The study protocol was approved by Bioethics Com-
mittee of our institution. Therefore the study has been
performed in accordance with the ethical standards laid
down in the 1964 Declaration of Helsinki and its later
amendments. All patients gave their informed consent prior
to their inclusion in the study.
Conflict of interest None.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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